WO1998000108A1

WO1998000108A1 - Proflavine composition and applicator

Info

Publication number: WO1998000108A1
Application number: PCT/DE1997/001418
Authority: WO
Inventors: Hans-Thomas Luyken; Heinke Bock
Original assignee: Luyken Hans Thomas; Heinke Bock
Priority date: 1996-06-28
Filing date: 1997-06-30
Publication date: 1998-01-08
Also published as: DE29723113U1; DE19627340A1; AU3538297A

Abstract

A medicament contains at least one substance from the group of the proflavines and their derivatives, and contains in particular a proflavine hemisulphate for treating viral diseases, preferably for the ambulatory treatment of herpetiform diseases of the mouth and lips, in particular for treating herpes labialis. The applicator for this medicament has a rod-shaped element (20, 30, 40, 50) provided at least at one end with a spatula (31, 42) which acts as a support for the active substance contained in a transparent salve excipient and enables a photochemical treatment to be simultaneously applied.

Description

PROFLAVIN COMPOSITION AND DEVICE FOR THEIR APPLIKAΗON

description

The invention relates to the use of a pharmaceutical according to the preamble of claim 1 as a further indication and a device for its application. It is known that medicaments which contain substances from the group of proflavines and their derivatives, in particular proflavin hemisulfate (chemical name: 3,6-diamoacridine sulfate dihydrate), have an antiseptic effect.

These preparations are therefore used successfully, preferably as a 0.1 to 1.0 percent aqueous solution, for the treatment of wounds and burns or also for local infections of the outer ear or mouth and throat area, in order to prevent inflammation, by a bacterial To prevent processes caused by influence or at least to weaken them to a high degree.

Many diseases, in particular also relatively widespread diseases of the skin area, can also be traced back to the influence of viruses.

In the essay by Lytle, CD .; Carney, P.G .; Feiten, R.P .; Bushar, H.F .; and Straight, R.C .: "Inactivation and mutagenesis of herpes virus by photodynamic treatment with therapeutic dyes" in Off. Be. Technol., Dcent. Devices Radiol. Health, Rockville, MD 20857 USA, describes an effect of proflavin on herpes viruses with simultaneous photc treatment, in particular in animal experiments.

However, application in humans has so far been ruled out because of the lack of usable application options.

The invention is therefore based on the object of providing a possibility for the successful treatment of virally caused skin diseases, in particular of herpitiform diseases of the skin in the mouth and lip area, which can be carried out with simple means and leads to a healing effect in the short term. The object is achieved by the features specified in claim 1.

The invention includes the surprisingly found finding that preparations containing proflavin and corresponding derivatives, in particular proflavin hemisulfate (3,6-diamoacridine sulfate dihydrate), have antiviral effects, advantageously for the external treatment of herpitiform diseases of the skin in the skin The area of the mouth and lips, especially a labial herpes, can be used if they are applied appropriately.

The herpitiform diseases in the mouth and lip area are expressed by blisters grouped on reddened ground, which dry up to crusts. They are particularly uncomfortable for the ■ affected patient, since they are often associated with severe itching and a more or less pronounced feeling of tension.

The effect of the use of proflavin hemisulfate for the treatment of the above-mentioned skin diseases is enhanced by a further medical effect which is particularly advantageous for the patient, which is expressed in that the skin areas treated with proflavin hemisulfate are demonstrably not or in a few cases only after a period of more than two years.

In accordance with the preferred embodiment of the invention, the proflavine hemisulfate is used in a mixture with a neomcym sulfate and - after appropriate preparation - applied in the form of a phototransparent ointment.

The active ingredient in the ointment is combined with a spatula-shaped applicator, which allows the

Active ointment without rubbing or smearing to be transferred in flat contact by hanging up immediately. The phototransparent ointment substrate thus forms the mechanical carrier for the active ingredient on the one hand to keep it in the area of application for the time of the aftertreatment, and on the other hand represents a translucent filter that allows the access of light that catalytically favors the actual effect.

According to an advantageous development of the invention, the proflavin hemisulfate preparation in the form of an adhesive ointment based on glycerol is used for the external treatment of herpetic diseases of the skin in the area of the mouth and lips, in particular herpes labialis or genitalis.

According to a favorable further development of the invention, the adhesive ointment is produced in such a way that microfine powdered proflavin hemisulfate is mixed with neomycin sulfate and dissolved with the addition of aqua purificate. The ointment form chosen for convenient application of the antiviral active ingredient is created by the subsequent addition of Unguentum Glycirini. Unguentum Glycirini is added without the addition of heat, the entire mixture being processed into an ointment with stirring.

It was found that proflavin hemisulfate and neomycin sulfate in a ratio of 1 to 5 dissolved in a small amount of aqua purificata and mixed with Unguentum Glycerini to form an adhesive ointment with a sulfate content of about 0.5 to 0.8 percent, which can be applied particularly well. The aqua purificata used for the adhesive ointment according to the invention and the unguentum Glycerini have a purity of DAB 10 and DAB 6, respectively. In order to cover medical institutions' own needs, the processing of small quantities, for example 25 mg proflavin hemisulfate and 125 mg neomycin sulfate with the addition of a few drops of aqua purificata and Unguenurn Glycerini to 25 g of an adhesive ointment, is favorable.

According to another embodiment of the invention, the antiviral proflavin hemisulfate preparation is applied in the form of a gel. Application as a hydroxyethylcelulose gel (DAB 10) or as a glycerol gel (DAC) is particularly advantageous.

Since Proflavinhemisulfat is a substance that changes its properties when exposed to light energy, the adhesive ointment or gel must be manufactured as far as possible and stored completely without exposure to light.

For this reason, in accordance with another development of the invention, the adhesive ointment or the gel is filled into aluminum tubes provided with an interior protective lacquer or a light-tight film packaging. According to an additional development of the invention, the film packaging consists of a light-tight carrier film which has a plurality of cup-like formations, each pointing in the same direction, into which an approximately pea-sized amount of the adhesive ointment or gel according to the invention is positioned. The cup-like formations are individually provided with a film cover, which is also light-tight. The film cover has a short grip tab, with the use of which the film cover can be easily removed from the respective shape. After removing the film cover, the adhesive ointment can be conveniently used using a rod-shaped tools can be removed. The rod-shaped aid can also be used to apply the adhesive ointment to the diseased area of the skin.

In order to always have the rod-shaped aids required for application at hand, the film packaging is designed in two parts in accordance with another favorable embodiment of the invention and contains a first partial area for the adhesive ointment or gel portions and a second partial area in which the rod-shaped Aids are arranged.

The rod-shaped aids are each positioned in an elongated shape of the carrier film and are secured against falling out by a correspondingly large film cover. The foil cover can be easily removed with a handle to allow quick access to the rod-shaped tools.

The rod-shaped aids are preferably designed as a round rod made of wood or plastic. They merge into a spatula at the ends - on one or both sides. Round rods, which are designed as described above, ensure particularly easy handling when applying the ointment according to the invention, since the ointment can be removed from the shape of the packaging with one of the ends and applied to the skin area to be treated, and excess ointment residues can be applied with the other end can be easily removed by ablation.

The film packaging has a plurality of predetermined breaking points or predetermined breaking points which define the areas for the portioned active ingredients and the rod-shaped aids. structure in a triangular shape. As a result, individual portions of active ingredient and rod-shaped aids can advantageously be separated out from the film packaging, so that the patient does not constantly have to carry the entire packaging.

In particular, it is favorable if the spatula is convex on its side that applies the ointment, and it can be provided with sieve-like openings. In this case, the ointment on the side opposite the convex side of the spatula is then kept in stock for passage through the sieve.

On the side opposite the convex side of the spatula, a convex pressure element is advantageously held, which is mounted adjacent to the spatula for pushing the ointment through the sieve.

For easy handling, it is particularly favorable if the spatula and the pressure element are connected to one another in the form of tweezers.

In the case of a solution with its own worthy of protection, the application device is designed in such a way that at least the spatula is light-guiding, which is connected to a light source via a light guide guided along its shaft area, the shaft area itself advantageously being light-guiding and at least indirectly with a light source can be connected.

It is also favorable for an ergonomic design if the spatula has such a prismatic structure that the light incident from the shaft area is diverted at right angles through the adhesive ointment.

The medicament with the applicator is preferably packaged in such a way that the spatula forms a disposable article which is packaged, in particular individually, with the portioned ointment.

In addition, there is advantageously provided a (reusable) timer for the light source connected to the light-conducting spatula, which enables the setting of an exposure period in the range from a few minutes to an hour. The timer with the light source can thus be permanently available in the medical practice as a one-time purchase, while a ready-made "set" is required for the treatment, which has a light-conducting spatula carrying the ointment in sterile packaging. The design as a disposable article ensures hygienic use.

Other advantageous developments of the invention are characterized in the subclaims or are shown below together with the description of the preferred embodiment of the invention with reference to the figures. Show it:

FIG. 1 shows an advantageous embodiment of a packaging with the medicament containing the active substance according to the invention and devices for its application in plan view,

FIG. 2 shows a sectional illustration along the line A ... A, according to FIG. 1, FIGS. 3a to 3d further advantageous embodiments of devices for the application of the drug according to the invention,

Figures 4a and b an advantageous embodiment of a further application device for the invention

Medicines in side view and top view,

Figure 5 shows an advantageous variant of the device shown in Figures 4a and b and

6 shows a control device for a device according to FIG. 4 or 5 in the block diagram.

In an advantageous embodiment, the medicament according to the invention is produced according to the following recipe: neomycin sulfate 0.125 proflavine hemisulfate 0.025

Aqua purificata q.s.

Unguentum Glycerini ad 25.00

In an ointment bowl tared with the pestle, 0.125 grams of neomycin sulfate and 0.025 grams of proflavine hemisulfate are microfine powdered and then dissolved in a few drops of Aqua purificata DAB 10.

It is supplemented with Unguentum Glycerini DAB 6 to 25.00 grams and the whole thing is processed into a practically odorless, yellow-orange colored adhesive ointment without heating with stirring and frequent scraping of the recipe sticking to the shell wall and pestle.

The ointment surface looks uniform and should not recognize any active ingredient crystals or crystal aggregates. - solve

sen. Proflavin hemisulfate was found to be light sensitive (although this light sensitivity does not interfere with subsequent photo treatment). The production should therefore be carried out in a place protected from intense light and without delay. If there is an unavoidable break in work, the approach must be protected from light.

However, the ointment base is transparent for the later photo treatment at least for long-wave UV radiation, so that the applied ointment can be exposed by means of a light source.

On an industrial scale, production takes place in corresponding mass multiples, with the corresponding processing and mixing devices from the pharmaceutical industry being used.

The advantageous effect of the preparation together with the applicator is based on the fact that the active ingredient can be gently applied to the diseased areas of the skin using the spatula, since no rubbing or smearing is necessary for this. The active ingredient remains in adherent contact with the skin surface through the ointment layer while the exposure takes place. Because the ointment is phototransparent, it allows enough light to penetrate the treated skin surface to allow the healing effects of the combination of a physical and a chemical effect to occur.

FIG. 1 shows a top view of a film packaging 1 for a proflavin hemisulfate preparation in ointment form. The packaging 1 is subdivided into two areas 1 ′, 1 ″, in which individually packaged portions 2 of the preparation or individually packaged rod-shaped auxiliary means 40 are summarized for applying the preparation. The predetermined breaking or predetermined breaking lines 10, 11, 12 structure the film packaging 1 in a matrix and allow individual portions 2 of the preparation to be separated, each with a rod-shaped aid 40 required for application.

The view shown in FIG. 2 of a section along the line A ... A corresponding to FIG. 1 shows the structure of the film packaging 1, which has a carrier film 4 with cup-like or cuboid-like formations 7, 8 for receiving the proflavine hemisulfate preparation 9 or the rod-shaped tool 40 for applying the preparation 9. The formations 7, 8 are each individually closed by a film cover 5, 6. The grip tabs 5.1 and 6.1 allow the respective film cover 5, 6 to be removed conveniently, so that individual portions of the preparation 9 can be removed and applied to the skin sections to be treated with the rod-shaped aid 40.

The rod-shaped aids 20, 30, 40, 50 for applying the proflavin hemisulfate preparation to the skin sections to be treated are shown in FIGS. 3a, 3b, 3c and 3d.

The tools have a round rod 22, 32, 43, 53 made of wood or a plastic. The ends of the round rod are provided on both sides with spatula-shaped elements 31, 42 or 52 for applying the proflavin hemisulfate preparation. Depending on the patient's needs, one end of the rod is used to apply the ointment or gel portion to the diseased areas of the skin, whereas the other end of the round rod can be used to remove any excess amount of preparation. For this is in In the case of the embodiment shown in FIG. 3c, a spatula-shaped element is also provided.

It is important that the spatulate elements as

Serve carriers of the ointment, which can be placed on the diseased skin area in this way by placing it directly without smearing it on the side.

In the embodiment shown in FIG. 3b, the spatula 31 is convex on its side that applies the ointment. This enables a particularly ergonomic transfer of the ointment base carrying the active ingredient. In all cases, the spatulas are preferably disposable items which are packaged with ointment that has already been applied in portions.

4a and b show a further embodiment 60 of the invention, in which the convex spatula is provided with sieve-like openings. A portion of ointment is portioned on the side opposite the convex side of the spatula for passage through the sieve. In particular, a light guide 63 is fastened to one of two webs 61 and 62 connected to one another via a flexible region by means of clips 64 and 65. The convex curved spatula region 66 is arranged adjacent to a counter element 67, which is provided with a stiffening web 68. In the assembled form as a disposable packaging, the counter element 67 carries the ointment, which forms a coating to be pressed through holes 69 of the sieve-shaped spatula element 66 when the tweezers are pressed together.

In FIG. 4b, a side view shows how the ointment 71 swells through the holes 69 when the tweezers are pressed together and can thus be applied conveniently. A convex pressure element is thus held on the side opposite the convex side of the spatula which serves to push the ointment through the sieve. The spatula and the pressure element are connected to one another in the form of tweezers or pliers for easy handling.

At least the spatula is designed to be light-guiding, wherein it is connected via a light-guiding device which is guided along its shaft region to a light source (not shown in the drawing) which emits light with a wavelength of preferably 450 nm.

In a further embodiment shown in FIG. 5, the shaft region (web) is also designed to be light-guiding as a support for the spatula and is at least indirectly connected to a light source (also not shown in the drawing). The shaft region is in one piece (with the spatula) made of transparent plastic and has a plug terminal 75 for a light ^¬ on conductor cable, which leads to a cold light source. the latter is also reusable.

In addition, the spatula shown in FIG. 5 has a prismatic structure 73 on its underside, which deflects the light incident from the shaft area essentially at right angles through the adhering ointment. The pressure surface 74 has a corresponding prismatic structure in order to fill out the prismatic structure 73 with respect to the ointment.

In FIG. 6, an arrangement is shown schematically as a block diagram, which includes a time selection block 81. adjustable timer device 80, which controls a driver stage 82 for a light source 83, which causes radiation 84.

The presettable timer for the light source to be connected to the light-conducting spatula is the set of instruments that are available in the medical practice and are purchased once. The ointment made up with the spatula as a disposable item is used in portions for each patient and removed from the sterile packaging.

In the following, some observations are described when using the known substance proflavin (according to the recipe) for herpetic diseases of the mouth and lips:

It was found that healing with the medication described here is faster and more thorough than with comparable means (for example Zovirax). A previously observed relapse could not be found at the treated area.

The ointment was applied to the diseased area of the skin several times on successive days.

The ointment is applied by applying with a double-sided spatula in order to then remove the ulcer (excess) with the clean side of the spatula.

The effect could be achieved by the simultaneous application of UV light (e.g. dental lamp), especially long-wave UV light. A preferred application is for a light wavelength of 450 nm.

The effect described above was among others in people who suffered from recurrent herpes labialis and could not achieve any improvement with the known means (including Zovirax).

The herpes labialis healed briefly, and no further illness has occurred since then (within two years).

In self-tests, no other illness has occurred since the start of use about two years ago.

With this application there is an effect that more or less excludes a - previously common - re-disease on and on the affected skin area. Treatment is not limited to the current indication. The application in other indications for the treatment of other diseases (herpes II lesions - carcinomas) is seriously considered. The packaging in the packaging described above is carried out (under light protection) as follows:

The adhesive ointment is preferably filled into an aluminum tube with an interior protective coating.

For "pro-ordination" recipes, pea-sized portions are shrink-wrapped in small, square foils, whereby for application with a spatula, the latter are individually aseptically shrink-wrapped in foils.

There are other possibilities in the preparation as a gel, glycerol gel (DAC) in particular being used as the gel base. Preparation with hydroxyethyl cellulose gel (DAB 10) is also possible.

Phototherapy is based on the principle that photoactive dyes are stimulated by light energy devices. The light energy absorbed for this is released as chemical energy, which leads to an oxidation of the virus DNA and to an inactivation of the virus. For this purpose, 0.1% Proflavin solution is applied to open cold sores. The light from a 15 to 100 watt incandescent lamp from a short distance (15-20 cm) should act for 15-30 minutes; after 6-8 h repetition of the radiation; preferably over several days. With frequent herpes solaris preventive use of light protection ointments.

The embodiment of the invention is not limited to the preferred exemplary embodiments specified above. Rather, a number of variants are conceivable which make use of the solution shown, even in the case of fundamentally different types. In particular, it is important that the application device with light guide for photochemical therapy forms a solution with its own worthy of protection, which can also be used independently of the medicament shown here. The device is particularly suitable as an applicator for metering ointments with a photochemical effect in the

Connection with all effluent viral diseases.

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Claims

Expectations

1. Medicament with at least one substance from the group of proflavins or their derivatives, in particular a proflavin hemisulfate, characterized by the use for the treatment of viral diseases in a skin surface area accessible to exposure with a translucent or at least long-wave UV radiation not significantly absorbing an adherence without Smear or rub ointment base.

2. Medicament according to claim 1, characterized by the use of unguentum glycerini as an ointment base.

3. Medicament according to claim 1, characterized in that the light wavelength is essentially 450 nm.

4. Medicament according to claim 2, characterized by proflavine hemisulfate in a mixture with a neomycin sulfate.

5. Medicament according to claim 3 in the form of an adhesive ointment based on glycerol or a glycerol or hydroxyethyl cellulose gel.

6. Medicament according to one of the preceding claims, characterized by a portioned, aseptic packaging kung (1, 1 ', 2), which is provided in particular as a welded carrier film (4) or as a tube.

7. Medicament according to one of the preceding claims, characterized in that the packaging is substantially opaque to light.

8. Medicament according to claim 7, characterized in that the carrier film (4) has cup-shaped depressions (7) for preferably approximately pea-sized individual portions (2) of the ointment or gel (9), each for the individual depressions (7) a separate film cover (5) is provided.

9. Medicament according to one of claims 7 or 8, characterized in that in the film packaging (1) at least one rod-shaped element (20, 30, 40, 50) for handling individual portions (2) of the ointment or gel (9th ) are included and stored in cuboid form (8) closed by a separate film cover (6).

10. Medicament in particular according to claim 9, characterized in that the rod-shaped element (20, 30, 40, 50) as an application device for an active ingredient for simultaneous photochemical treatment on at least one of its ends a spatula (31, 42) as a carrier for the active ingredient with ointment base.

11. Medicament or application device according to claim 10, characterized in that the rod-shaped element as a round rod (22, 32, 43, 53) are made of wood or plastic.

12. Medicament or application device according to claim 11, characterized in that the spatula is convex on its side applying the ointment.

13. Medicament or application device according to claim 12, characterized in that the spatula is provided with sieve-like openings, the ointment being attached to the side opposite the convex side of the spatula for passage through the sieve.

14. Medicament or application device according to claim 13, characterized in that on the opposite side of the convex side of the spatula, a convex pressure element is held, which is the spatula for pushing the ointment through the sieve adjacent.

15. Medicament or application device according to claim 14, characterized in that the spatula and the pressure element are connected to one another in the form of tweezers.

16. Medicament or application device according to claim 13, characterized in that at least the spa tel is formed light-guiding, which is connected to a light source via a light guide guided along its shaft region.

17. Medicament or application device according to claim 16, characterized in that the shaft area is itself light-guiding and is at least indirectly connected to a light source.

18. Medicament or application device according to claim 17, characterized in that the spatula has a prismatic structure which deflects the light incident from the shaft area substantially at right angles through the adhering ointment.

19. Medicament or application device according to one of the preceding claims, characterized in that the spatula forms a disposable article which is packaged with portioned applied ointment, in particular individually.

20. Medicament or application device according to one of the preceding claims, characterized in that a timer is provided for the light source connected to the light-conducting spatula, which enables the presetting of an exposure period in the range from a few minutes to an hour.

21. A process for the preparation of a medicament according to any one of the preceding claims, characterized in that microfine powdered proflavin hemisulfate is mixed with neomycin sulfate and brought into solution with the addition of aqua purificate and then processed with Unguentum Glycerini without adding heat with stirring to an ointment .

22. The method according to claim 12, characterized in that proflavin hemisulfate and neomycin sulfate in a ratio of 1 to 5 dissolved in a small amount of aqua purificata and mixed with Unguentum Glycerini to form an adhesive ointment with a sulfate content of about 0.5 to 0.8 percent become.

23. The method according to claim 13, characterized in that the aqua purificata has a purity of DAB 10 and the Unguentum Glycerini has a purity of DAB 6.

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